The statin class of drugs has been shown to reduce stroke and myocardial infarction in patients with hypercholesterolemia. Intriguingly, the statins have been shown to accomplish this not only by reducing cholesterol levels, but also by improving nitric oxide bioactivity and thereby reversing endothelial dysfunction in human subjects. Atorvastatin is one of the most widely prescribed drugs in the United States, with a well-characterized and very acceptable side effect profile. Our group and others have published evidence that approximately half of patients with sickle cell disease have physiological and biochemical evidence of impaired nitric oxide bioavailability. This appears to contribute to impaired regional blood flow in patients with sickle cell disease, particularly during vaso-occlusive episodes. Therefore, it is attractive to test atorvastatin for its hypothetical ability to restore nitric oxide dependent blood flow in patients with sickle cell disease. We are measuring forearm blood flow by plethysmography to determine the response to infusion of L-NMMA, a nitric oxide synthase inhibitor, to which sickle cell patients have a blunted response. After four weeks of oral outpatient atorvastatin therapy, this study is repeated, with increased responsiveness to L-NMMA as the primary outcome variable. Atorvastatin-induced alterations in blood flow to acetylcholine and to nitroprusside are also being evaluated. Additional secondary studies are evaluating the degree to which the elevated level of xanthine oxidase in sickle cell patients inhibit nitric oxide-mediated blood flow; markers of inflammation and oxidation; and gene expression by microarray and pilot studies of proteomics in sickle cell patients. In addition, endothelial progenitor cells (EPC) in circulating blood are being reserached, which are indicative of vascular health in the general population. As of 28 October 2003, we obtained IRB approval to begin these studies. We began enrollment in March 2004. Subjects with SCD with features of vasculopathy were selectively recruited if they had higher than median plasma levels of soluble VCAM-1, tricuspid regurgitant jet velocity (TRV) greater than or equal to 2.5 meters per second (m/s), or previous demonstration of impaired vasodilatory response to a nitric oxide donor. Twenty-four adult subjects with HbSS and 10 control subjects underwent measurement of baseline EPC levels in peripheral blood. The SCD subjects were then treated with a 4-week course of atorvastatin, with a repeat measurement of circulating EPC levels. TRV was measured by Doppler echocardiography before and after atorvastatin treatment. Subjects with SCD (n=24) had significantly fewer circulating EPCs than African-American control subjects (n=10) at baseline, (8.9 plus or minus 12.5 vs. 24.7 plus or minus 31.1 colonies per well, mean plus or minus SEM, p less than 0.05). SCD subjects with lower than median EPC number (less than 2.5 colonies per well) had a significantly higher serum alkaline phosphatase level than higher EPC patients (111 plus or minus 51 vs. 75 plus or minus 24 units per liter, p=0.03), a previously published independent correlate of pulmonary hypertension. SCD subjects with lower EPC number showed a trend towards higher TRV (2.6 plus or minus 0.3 vs. 2.4 plus or minus 0.2 m/sec, p=0.09). In males with SCD, EPC number positively correlated with serum C reactive protein (r=0.82, n=11, p=0.006). Finally, atorvastatin therapy did not increase EPC number in SCD subjects from baseline after 2 or 4 weeks of therapy (9.9 plus or minus 13.9 vs. 5.4 plus or minus 9.1 vs. 4.9 plus or minus 7.2 colonies per well, p=0.46), and it did not change TRV (2.5 plus or minus 0.1 vs. 2.5 plus or minus 0.1 m/sec). Atorvastatin or oxypurinol therapy did not significantly change frearm blood flow. Compared to African-American controls, subjects with SCD have much lower circulating EPC number, a new indicator of poor vascular health in these subjects. SCD subjects with lower EPC number show a pattern of overlap with markers of pulmonary hypertension. These findings are consistent with a role for low EPC number, as a marker of or contributor to vascular dysfunction and pulmonary arterial hypertension in patients with SCD, but rather further study is needed. Lastly, treatment with atorvastatin did not improve EPC number or pulmonary hypertension in a four-week course of treatment.